Sperm DNA damage and paternal age, "Beyond the Abstract," by Armand Zini, MD

BERKELEY, CA (UroToday.com) - There is now good evidence to show that sperm DNA and chromatin defects are associated with male infertility and a reduced probability of natural conception.[1, 2] Sperm DNA damage has also been associated with lower pregnancy rates after assisted conception (e.g., in-vitro fertilization or IVF) and with an increased risk of pregnancy loss after IVF.[3] Although the exact etiology of sperm DNA damage has not been established conclusively, advanced paternal age and poor sperm parameters are two factors that have often been related to this damage.[4, 5, 6, 7] Various mechanisms have been proposed to explain the increase in sperm DNA damage with age, ranging from oxidative stress to inefficient apoptosis processes.[8]

Many studies have reported a relationship between sperm DNA damage and advanced paternal age, but the main limitation of these studies is that they have evaluated infertile men with poor semen quality. As such, it is hard to ascertain that the relationship between paternal age and sperm DNA damage is independent of the relationship between paternal age and conventional semen parameters, or the severity of infertility. Therefore, we evaluated the relationship between sperm DNA damage and paternal age in a subgroup of men with normal semen parameters (normozoospermia) in order to minimize the influence of semen quality on DNA damage. We also compared the prevalence of sperm DNA damage in younger and older men with normozoospermia.

We obtained semen from 277 consecutive non-azoospermic men presenting for sperm DNA testing. The two main indications for sperm DNA testing in these men were:

(a) for evaluation of unexplained couple infertility, and
(b) for prediction of assisted conception outcomes.

These indications were based on prior publications suggesting a potential clinical role for sperm DNA testing.[9] Standard sperm parameters (concentration, %progressive motility, %strict morphology) were measured as per recent WHO guidelines.[10] The main outcome measures included paternal age, sperm % DNA fragmentation index (%DFI, using sperm chromatin structure assay), sperm concentration, progressive motility and morphology. The institutional ethics review board at McGill University approved this study.

We found that sperm % DFI was positively correlated with paternal age (r=0.20, P< 0.001) and inversely correlated % progressive motility (r=-0.16, P=0.01). Sperm %DFI was significantly higher in older (≥ 40 years) compared to younger (< 40 years) normozoospermic men (17 ± 13 vs. 12 ± 8, respectively P=0.008), whereas, sperm concentration, progressive motility, and morphology were not significantly different in these two groups. Moreover, the prevalence of high levels of sperm DNA damage (> 30% DFI) was significantly higher in older compared to younger normozoospermic men (17% vs. 3%, respectively, P< 0.001).

Our study demonstrates that sperm DNA damage is positively correlated with age. Moreover, our data indicate that the prevalence of isolated sperm DNA damage (> 30% DFI and normozoospermia) in infertile men is significantly higher in older compared to younger men (17% vs. 4%, respectively). The high levels of sperm DNA damage in older normozoospermic men may be associated with reduced male reproductive potential and may also, possibly, be an indicator of de novo genetic mutations.[11] Taken together, the data suggest that a conventional sperm analysis alone may fail to detect a defect in spermatogenesis in older men. Evaluation of sperm DNA damage may help to uncover a defect in spermatogenesis in older men and define the most appropriate method of assisted conception for these couples.

References:

  1. Evenson, D.P., Jost, L.K., Marshall, D., Zinaman, M.J., Clegg, E., Purvis, K., de Angelis, P., Claussen, O.P., 1999. Utility of the sperm chromatin structure assay as a diagnostic and prognostic tool in the human fertility clinic. Hum Reprod 14, 1039-1049.
  2. Spano, M., Bonde, J.P., Hjollund, H.I., Kolstad, H.A., Cordelli, E., Leter, G., 2000. Sperm chromatin damage impairs human fertility. The Danish First Pregnancy Planner Study Team. Fertil Steril 73, 43-50.
  3. Zini, A., Boman, J.M., Belzile, E., Ciampi, A., 2008. Sperm DNA damage is associated with an increased risk of pregnancy loss after IVF and ICSI: systematic review and meta-analysis. Hum Reprod 23, 2663-2668.
  4. Giwercman, A., Richthoff, J., Hjollund, H., Bonde, J.P., Jepson, K., Frohm, B., Spano, M., 2003. Correlation between sperm motility and sperm chromatin structure assay parameters. Fertil Steril 80, 1404-1412.
  5. Moskovtsev, S.I., Willis, J., Mullen, J.B., 2006. Age-related decline in sperm deoxyribonucleic acid integrity in patients evaluated for male infertility. Fertil Steril 85, 496-499.
  6. Moskovtsev, S.I., Willis, J., White, J., Mullen, J.B., 2009. Sperm DNA damage: correlation to severity of semen abnormalities. Urology 74, 789-793.
  7. Wyrobek, A.J., Eskenazi, B., Young, S., Arnheim, N., Tiemann-Boege, I., Jabs, E.W., Glaser, R.L., Pearson, F.S., Evenson, D., 2006. Advancing age has differential effects on DNA damage, chromatin integrity, gene mutations, and aneuploidies in sperm. Proc Natl Acad Sci U S A 103, 9601-9606.
  8. Singh, N.P., Muller, C.H., Berger, R.E., 2003. Effects of age on DNA double-strand breaks and apoptosis in human sperm. Fertil Steril 80, 1420-1430.
  9. Zini, A., Sigman, M., 2009. Are tests of sperm DNA damage clinically useful? Pros and cons. J Androl 30, 219-229.
  10. Cooper, T.G., Noonan, E., von Eckardstein, S., Auger, J., Baker, H.W.G., Behre, H.M., Haugen, T.B., Kruger, T., Wang, C., Mbizvo, M.T., Vogelsong, K.M., 2010. World Health Organization reference values for human semen characteristics. Human Reproduction Update 16, 231-245.
  11. Kong, A., Frigge, M.L., Masson, G., Besenbacher, S., Sulem, P., Magnusson, G., Gudjonsson, S.A., Sigurdsson, A., Jonasdottir, A., Jonasdottir, A., Wong, W.S., Sigurdsson, G., Walters, G.B., Steinberg, S., Helgason, H., Thorleifsson, G., Gudbjartsson, D.F., Helgason, A., Magnusson, O.T., Thorsteinsdottir, U., Stefansson, K., 2012. Rate of de novo mutations and the importance of father's age to disease risk. Nature 488, 471-475.

 

Written by:
Armand Zini, MD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

Division of Urology, Department of Surgery, McGill University, Montreal, Quebec, Canada
St. Mary’s Hospital, 3830 Lacombe Ave., Montreal, Quebec, Canada, H3T 1M5

High prevalence of isolated sperm DNA damage in infertile men with advanced paternal age - Abstract

More Information about Beyond the Abstract